Hollow copper sulfide nanoparticles carrying ISRIB for the sensitized photothermal therapy of breast cancer and brain metastases through inhibiting stress granule formation and reprogramming tumor-associated macrophages  

作　　者：Fan Tong Haili Hu Yanyan Xu Yang Zhou Rou Xie Ting Lei Yufan Du Wenqin Yang Siqin He Yuan Huang Tao Gong Huile Gao 

机构地区：[1]Key Laboratory of Drug Targeting and Drug Delivery Systems,West China School of Pharmacy,Sichuan University,Chengdu 610041,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第8期3471-3488,共18页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82173762,China);the Key Research and Development Program of Science and Technology Department of Sichuan Province(2022YFS0334,2022JDJQ0500,China);111 Project(B18035,China);the Fundamental of Research Funds for the Central Universities。

摘　　要：As known,the benefits of photothermal therapy(PTT)are greatly limited by the heat tolerance of cancer cells resulting from overexpressed heat shock proteins(HSPs).Then HSPs further trigger the formation of stress granules(SGs)that regulate protein expression and cell viability under various stress conditions.Inhibition of SG formation can sensitize tumor cells to PTT.Herein,we developed PEGylated pH(low)insertion peptide(PEG-pHLIP)-modified hollow copper sulfide nanoparticles(HCuS NPs)encapsulating the SG inhibitor ISRIB,with the phase-change material lauric acid(LA)as a gatekeeper,to construct a pH-driven and NIR photo-responsive controlled smart drug delivery system(IL@H-PP).The nano medicine could specifically target slightly acidic tumor sites.Upon irradiation,IL@H-PP realized PTT,and the light-controlled release of ISRIB could effectively inhibit the formation of PTT-induced SG to sensitize tumor cells to PTT,thereby increasing the antitumor effect and inducing potent immunogenic cell death(ICD).Moreover,IL@H-PP could promote the production of reactive oxygen species(ROS)by tumor-associated macrophages(TAMs),repolarizing them towards the M1 phenotype and remodeling the immunosuppressive microenvironment.In vitro/vivo results revealed the potential of PTT combined with SG inhibitors,which provides a new paradigm for antitumor and antimetastases.

关 键 词：Hollow coppersulfide nanoparticles Sensitized PTT SG inhibition TAMs repolarization pH-driven targeting Photothermal responsiveness Immunotherapy Anti-metastases 

分 类 号：R73[医药卫生—肿瘤]